Our core concept is that RLS is related to an underlying problem in iron utilization. This may be specific to the brain or a region of the brain, or may be a general systemic problem with different organs having different abilities to compensate. We do not believe that there is one defect for all; rather, we believe that several problems in iron metabolism will eventually be found to contribute to this syndrome. The long-term goal of this proposal is to establish the importance of brain iron metabolism in RLS by relating changes in the CNS iron status to changes in the clinical aspects of RLS patients; and to provide improved treatment for RLS. In this grant we focus on the use of intravenous iron as a potential long-term treatment option for this syndrome. We also address the question of whether there is increased iron loss and whether there are likely to be problems of iron overload or excessive oxidative stress with iron treatment. The specific aims of the current proposal are: Aim 1. To evaluate the ability to sustain for 2 years the initial therapeutic benefit of 1,000 mg of IV iron with iron versus placebo "supplemental" therapy. Aim 2. To evaluate putative mechanisms behind the rapid decrease in ferritin following intravenous (IV) iron treatment of RLS patients. Aim 3. To determine possible adverse effects from the IV iron treatment. Aim 4. To explore the effects of supplemental IV iron on patients who are non-responders to the initial 1000-mg IV iron dose.